Phase 1 Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid in Combination With Polatuzumab (ViPOR-P) in Relapsed/Refractory B-cell Lymphoma
Background: Aggressive B-cell lymphomas can be cured but people with disease that resists treatment or that returns after treatment have poor outcomes with standard therapies. Indolent B-cell lymphomas are generally incurable with standard therapy and treatment is aimed at controlling symptoms and achieving a durable remissions. Researchers want to see if a combination of drugs can help patients with both aggressive and indolent B-cell lymphomas.
Objective: To learn if it is safe and effective to give polatuzumab along with venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide to people with certain B-cell lymphomas.
Eligibility: Adults ages 18 and older with relapsed and/or refractory B-cell lymphoma who have had at least one prior cancer treatment.
Design: Participants will be screened with: Medical history Physical exam Assessment of how they do their daily activities Blood and urine tests Heart function test Tissue biopsy (if needed) Body imaging scans (may get a contrast agent through an intravenous (IV) catheter) Participants will have a bone marrow aspiration and/or biopsy. A needle will be put into the hipbone. Bone marrow will be removed. Participants may give blood, tissue, saliva, or cheek swab samples. They may have optional biopsies. Screening tests will be repeated during the study. Treatment will be given for up to 6 cycles. Each cycle lasts 21 days. Participants will take venetoclax and prednisone tablets by mouth. They will take ibrutinib and lenalidomide capsules by mouth. They will get obinutuzumab and polatuzumab by IV infusion. They will keep a medicine diary. Participants will visit the clinic 30 days after treatment ends. They will have follow-up visits for 5 years. If needed, they can visit their local doctor instead. They may be contacted by phone, mail, etc., for the rest of their life....
⁃ Patients must have histologically or cytologically confirmed B-cell lymphoma confirmed by the Laboratory of Pathology, NCI, as follows:
• Cohorts 1 and 2:
⁃ Aggressive B-cell lymphoma: includes DLBCL and subtypes, transformed lymphoma, Burkitt lymphoma, as well as high-grade B-cell lymphoma with MYC and/or BCL2 and/or BCL6 rearrangement(s).
⁃ Indolent B-cell lymphoma: with the following exceptions:
∙ MCL is excluded given increased risk of tumor lysis syndrome (TLS) with venetoclax compared to other non-Hodgkin lymphomas and need for venetoclax ramp-up, dose-escalation.
‣ CLL/SLL is excluded given alternative dosing of FDA-approved venetoclax for relapsed CLL/SLL and increased risk of TLS with CLL/SLL compared to other non-Hodgkin lymphomas.
• Cohort 3:
• Non-GCB DLBCL: includes DLBCL NOS and subtypes, transformed lymphoma, THRLBCL, as well as high-grade B-cell lymphoma with MYC and/or BCL6 rearrangement(s).
• NOTE: Patients with known active CNS lymphoma are not eligible.
⁃ Relapsed and/or refractory disease after at least 1 prior treatment regimen, as follows:
∙ Aggressive B-cell lymphoma: relapsed after and/or refractory to at least 1 prior anthracycline-containing regimen
‣ Indolent B-cell lymphoma: relapsed after and/or refractory to at least 1 prior anti- CD20 antibody-containing regimen.
⁃ Patients must have evaluable disease by clinical exam (i.e., palpable lymphadenopathy, measurable skin lesions, etc.), laboratory assessment (i.e., lymphoma involvement of bone marrow or peripheral blood by morphology, cytology or flow cytometry), and/or imaging (measurable lymph nodes or masses on CT or MRI and/or evaluable FDG-avid lesions on PET).
• NOTE: Lesions that have been irradiated cannot be included in the tumor assessment unless unequivocal tumor progression has been documented in these lesions after radiation therapy.
• Age \>=18 years
• NOTE: Because no dosing or adverse event data are currently available on the use of polatuzumab in combination with venetoclax, ibrutinib, obinutuzumab, prednisone and Revlimid(R) in patients \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
⁃ ECOG performance status \<=2.
⁃ Adequate organ and marrow function as defined below unless dysfunction is secondary to lymphoma:
∙ absolute neutrophil count\* \>=1,000/mcL
‣ hemoglobin\* \>=8 g/dL
‣ Platelets \>=75,000/mcL
‣ INR \<=1.5 X institutional upper limit of normal (ULN) for patients not receiving therapeutic anticoagulation
‣ PTT/aPTT \<=1.5 X institutional ULN normal except if, in the opinion of the investigator, the aPTT is elevated because of a positive Lupus Anticoagulant, or a significant bleeding risk has been ruled out in the absence of a positive Lupus Anticoagulant
‣ total bilirubin \<=1.5 X institutional ULN (or \<=3 X institutional ULN for patients with documented Gilberts syndrome identified by an isolated unconjugated hyperbilirubinemia in the absence of other signs of liver dysfunction and/or UGT1A1 mutational testing)
‣ AST(SGOT)/ALT(SGPT) \<=3 X institutional ULN
‣ Serum creatinine \<=2.0 mg/dL OR
‣ Creatinine clearance \>=30 mL/min/1.73 m2 for patients with creatinine levels above 2 mg/dL
• NOTE: Cr Cl will be calculated with the use of the 24-hour creatinine clearance or eGRF in the clinical lab
⁃ RBC transfusions and use of G-CSF will be allowed in order to meet eligibility parameters.
∙ Immune-modulating drugs (IMiDs) including Revlimid(R) are known to be teratogenic and potential embryo-fetal harm can be seen with use of polatuzumab, venetoclax and ibrutinib. The effects of obinutuzumab on the developing human fetus is unknown. For these reasons, individuals of child-bearing potential and individuals able to father a child must agree to use adequate contraception as described below.
⁃ For individuals of childbearing potential:
∙ Agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of \< 1% per year as outlined below.
‣ Agreement to refrain from donating eggs during timelines specified below.
‣ Individuals of childbearing potential (ICBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior to prescribing Revlimid(R) for Cycle 1 (prescriptions must be filled within 7 days as required by Revlimid REMSTM) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking Revlimid(R) ICBP must also agree to ongoing pregnancy testing.
‣ An individual is considered to be of childbearing potential if that person is post-menarcheal, has not reached a postmenopausal state (\>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
‣ Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
‣ The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• For individuals able to father a child:
∙ Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
‣ With partners of childbearing potential, individuals able to father a child must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year as noted below. Individuals must refrain from donating sperm during this same period.
‣ With pregnant partners, individuals must remain abstinent or use a condom as noted below to avoid exposing the embryo.
‣ The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
‣ Contraception Requirements
⁃ Time frame/Study Drug (Pre-Treatment/During Treatment) - Individuals of childbearing potential (Time frame prior to/during dosing) / Individuals able to father a child (Time frame prior to/during dosing):
‣ --All drugs; Begins 28 days prior to treatment; Begins on day 1
• Time frame/Study Drug (Post-Treatment) - Individuals of childbearing potential (Time frame after the last dose) / Individuals able to father a child (Time frame after the last dose):
∙ Venetoclax - 90 days / 90 days
‣ Ibrutinib - 3 months / 3 months
‣ Obinutuzumab - 18 months / 6 months
‣ Revlimid(R) - 28 days / 28 days
‣ Polatuzumab - 3 months / 5 months
‣ All study participants must be registered into the mandatory Revlimid REMSTM program and be willing and able to comply with the requirements of Revlimid REMSTM. NOTE: Individuals of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMSTM program.
‣ Ability of subject to understand and the willingness to sign a written informed consent document.